Apparatus and methods for clot dissolution

ABSTRACT

Clot disruption and dissolution are achieved using a catheter having the ability to infuse a thrombolytic agent, aspirate clot and fluid, and allow passage of a guidewire. Optionally, the catheter may also include a mechanical agitator for further disrupt clot in the presence of the thrombolytic agent. A flow resistor in the catheter provides for infusion and/or aspiration to be concentrated primarily at a clot treatment area in a blood vessel while also providing optional infusion and/or aspiration distal to the treatment area. In some embodiments, infusion, aspiration and guidewire passage occur through a common lumen. The thrombolytic agent, such as tPA, streptokinase, or urokinase, is directly released into the clot at the point where the agitator is engaging the clot. In this way, the thrombolytic activity of the agent is enhanced and the dissolution of the clot is improved.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.10/142,005, filed on May 8, 2002, now U.S. Pat. No. 7,763,010, which isa continuation-in-part of U.S. patent application Ser. No. 09/491,401,filed on Jan. 25, 2000, now U.S. Pat. No. 6,663,613, and ofPCT/US01/02406, filed on Jan. 24, 2001, the full disclosures of whichare incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices and methods.More particularly, the present invention relates to devices and methodsfor dissolving and disrupting occlusive materials from blood vessels.

Thrombosis and atherosclerosis are common ailments which result fromdeposition of thrombus or atheromas, respectively, in the luminal wallsof blood vessels. When hardened, such deposits typically result invascular obstruction and reduced blood flow through the lumens ofaffected blood vessels. Thrombosis and atherosclerosis are most commonin the peripheral blood vessels that feed the limbs of the human bodyand the coronary arteries which feed the heart. Stasis, incompetentvalves, and trauma in the venous circulation cause thrombosis,particularly occurring as a deep vein thrombosis in the peripheralvasculature. When such deposits accumulate in localized regions of theblood vessel, they can restrict blood flow and cause a serious healthrisk.

In addition to forming in the natural vasculature, thrombosis is aserious problem in “artificial” blood vessels or autologous blood vesselgrafts, particularly in peripheral femoral-popliteal and coronary bypassgrafts and dialysis access grafts and fistulas. The creation of suchartificial blood vessels requires anastomotic attachment at least one,and usually at least two, locations in the vasculature. Such sites of ananastomotic attachment are particularly susceptible to thrombusformation due to narrowing caused by intimal hyperplasia, and thrombusformation at these sites is a frequent cause of failure of the implantedgraft or fistula. The arterio-venous grafts and fistulas which are usedfor dialysis access are significantly compromised by thrombosis at thesites of anastomotic attachment and elsewhere. Thrombosis often occursto such an extent that the graft needs to be replaced within a few yearsor, in the worst cases, a few months.

A variety of methods have been developed for treating thrombosis andatherosclerosis in the coronary and peripheral vasculature as well as inimplanted grafts and fistulas. Such techniques include surgicalprocedures, such as coronary artery bypass grafting, and minimallyinvasive procedures, such as angioplasty, atherectomy, thrombectomy,thrombolysis, transmyocardial revasculaturization, and the like.

Of particular interest to the present invention, a variety of techniqueshave been developed for dissolving clot using thrombolytic agents, suchas tissue plasminogen activator (tPA), streptokinase, urokinase, and thelike. While such thrombolytic agents can be delivered systemically, thepresent invention is most particularly concerned with the local deliveryof such agents and even more particularly concerned with the localdelivery of such agents in combination with mechanical clot disruption.

Thrombolytic agents can be very effective at attacking and dissolvingrelatively soft clot, such as that formed in deep veins. Such agents,however, require time to act, and local delivery catheters often employisolation balloons to provide high local concentrations of the activethrombolytic agents. Even with such enhanced concentrations, the agentscan take extended periods to act, rendering the treatments lengthy andinefficient. In some instances, extensive regions of clot simply cannotbe effectively treated using thrombolytic agents alone. In such cases,it has been further proposed to provide a mechanical element to disruptthe clot while the thrombolytic agents are being delivered. See, forexample, U.S. Pat. No. 5,947,985 to Mir A. Imran. This patent describesa catheter having axially spaced-apart balloons for isolating atreatment region within a blood vessel. The catheter includes a port fordelivering thrombolytic agent between the spaced-apart balloons and ahelical wire for removing clot material from the wall to assist inaspiration. While a promising technique, this catheter is not optimizedto enhance delivery and mixing of the thrombolytic agent directly intothe clot being treated.

For these reasons, it would be desirable to provide improved apparatus,methods, and kits for disrupting and dissolving vascular thrombosis,particularly soft clot of the type found in deep vein thrombosis. Itwould be particularly desirable to provide methods and apparatus whichcan enhance the thrombolytic activity of thrombolytic agents deliveredto the region being treated, and even more particularly enhance thedirect introduction into and mixing of the thrombolytic agent within themass of clot within the blood vessel. It would also be desirable toprovide methods and apparatus which provide infusion of thrombolyticagents, aspiration of fluid and/or clot, and passing of a guidewirethrough a common lumen, with a majority of infusion and aspirationoccurring through an opening in the lumen adjacent the clot. At leastsome of these objectives will be met by the inventions describedhereinafter.

2. Description of the Background Art

Clot disruption catheters which combine the delivery of thrombolyticagents with mechanical disruption are described in, for example, U.S.Pat. Nos. 5,972,019 and 5,947,985. Other clot disruption catheters aredescribed in, for example, U.S. Pat. Nos. 5,954,737; 5,795,322;5,766,191; 5,556,408; 5,330,484, 5,279,546; 5,116,352; 5,014,093; and WO96/01591. Catheters having axially spaced-apart isolation balloons fortreating thrombus are shown in, for example, U.S. Pat. Nos. 5,947,985and 5,279,546 and WO 97/11738. Catheters having helical and non-linearguidewires are described in U.S. Pat. Nos. 5,584,843; 5,360,432;5,356,418; and 5,312,427. Other patents and patent publications ofinterest include U.S. Pat. Nos. 6,346,116 B1, 6,312,444 B1, 5,957,901;5,951,514; 5,928,203; 5,908,395; 5,897,567; 5,843,103; 5,836,868;5,713,848; 5,643,228; 5,569,275; 5,549,119; 5,540,707; 5,501,694;5,498,236; 5,490,859; 5,380,273; 5,284,486; 5,176,693; 5,163,905;4,923,462; 4,646,736; and 4,445,509; and WO 99/23952 and WO 99/04701.Publications of interest in the medical literature include LeVeen et al.(1992), American Heart Association Poster Presentation; Tachibana (1993)JVIR S:299-303; Kandarpa et al. (1998) Radiology 168: 739-744; Bildsoeet al. (1989) Radiology 171: 231-233; and Ritchie et al. (1986)Circulation 73: 1006-1012.

BRIEF SUMMARY OF THE INVENTION

The present invention provides apparatus, methods, and kits fordisrupting and dissolving thrombus, also referred to as clot, present ina patient's vasculature, including both the arterial and venousvasculature, as well as grafts. The present invention is particularlyintended for treating thrombotic disease within the venous vasculature,such as thrombosis in the superficial vein, the central veins, thefemoral-popliteal veins, the iliofemoral vein, and the like. The presentinvention is also particularly intended for treating arterial thromboticdisease, such as thrombosis in the iliofemoral artery, the superficialfemoral artery, and the like.

The present invention is advantageous in a number of respects. Inparticular, the methods and apparatus of the present invention willprovide improved introduction and mixing of thrombolytic agents intovascular clot, which in turn will improve the efficiency of clotdissolution, including both reducing the time required for dissolutionand/or enhancing the degree to which the clot is dissolved, i.e.,reducing the particle size of clot achieved at the end of treatment. Thereduction of treatment time will reduce both the cost of treatment andthe time during which the patient is undergoing the treatment. Theimproved degree of clot dissolution will reduce the danger of releasedemboli, which can be a serious risk to the patient.

Various embodiments of the present invention provide apparatus andmethods for infusing thrombolytic agents, aspirating clot and/or fluid,and passing a guidewire through a common catheter lumen. Otherembodiments provide for separate lumens for infusing, aspirating and/orpassing a guidewire. Generally, the embodiments described provideadvantageous alternatives for accomplishing desired infusion, aspirationand/or positioning tasks during a clot disruption procedure. Embodimentswith only one or two lumens may provide the additional advantage ofhaving a relatively smaller diameter than other devices.

In a first aspect, apparatus for disrupting clot over a luminal lengthof a blood vessel according to the present invention comprises acatheter body having a proximal end, a distal end and at least onelumen. The lumen includes a distal-end opening for allowing passage of aguidewire and fluid flow and at least one side opening proximal to thedistal-end opening for allowing fluid flow. The distal-end opening andthe at least one side opening generally allow preferential fluid flowthrough the at least one side opening. The catheter body furtherincludes a first radially expandable body between the distal-end openingand the side opening in the lumen, for inhibiting flow of clot beyondthe luminal length of the blood vessel.

The dimensions and materials of the catheter body will be selectedaccording to the target site within the vasculature to be treated, i.e.,the catheter will be sized to be introduced percutaneously or via a cutdown to the vasculature at an entry and then be intravascularlyadvanced, typically over a guidewire, to the target site. Target sitesin the peripheral, coronary, and cerebral vasculature will generally beapproached through different access sites and will require cathetershaving different lengths, diameters, and flexibilities. Theconstructions of such catheters, however, are well-known andwell-described in the patent and medical literature.

The luminal length of the blood vessel will usually be at least 3 cm,more usually being at least 10 cm, and typically being in the range from3 cm to 100 cm, usually from 5 cm to 40 cm. The length of thromboticdisease being treated will vary depending on the location of the diseasewithin the vasculature. For example, deep vein thrombosis will often bedisseminated over a length in the range from 5 cm to 100 cm. Theapparatus and methods of the present invention will be capable oftreating disease disseminated over these lengths as described in moredetail below. The apparatus of the present invention need not be adaptedto treat the entire length of the diseased region at once. It will oftenbe possible and in some cases desirable to treat discrete lengths withinthe entire diseased region separately. Such discrete lengths can betreated successively, e.g., by axially translating the treatment devicewithin the blood vessel being treated. Alternatively, the segments couldbe treated using different devices, optionally introduced from differentintroduction sites in the vasculature.

In some embodiments of the invention, infusion of an agent, aspirationof clot and fluid, and/or passage of a guidewire may be performedthrough a common lumen. In other embodiments, two or more lumens areused for infusion, aspiration, and guidewire passage. For example, inone embodiment infusion and guidewire passage may occur through onelumen and aspiration may occur through another. In other embodiments,aspiration and guidewire passage may occur through the same lumen andinfusion may occur through another. Thus, some embodiments of thepresent invention provide for infusion and aspiration through thedistal-end opening and the at least one side opening, while otherembodiments divide these tasks among multiple lumens. Furthermore, manyembodiments of the invention allow for a guidewire to remain in placewithin the at least one lumen while either infusion, aspiration, or bothare performed through the distal-end opening and the at least one sideopening.

As described briefly above, the distal-end opening and the at least oneside opening are generally configured to allow for preferential fluidflow through the at least one side opening. This preferential flow maybe accomplished in any of a number of suitable ways. For example,distal-end opening may be configured to have a cross-sectional area thatis significantly smaller that the cross-sectional area of the at leastone side opening. In one embodiment, the distal-end opening may have across-sectional area of between about 0.1% and about 20%, and preferablybetween about 1% and about 5%, of the cross-sectional area of the atleast one side opening. This difference in cross-sectional areas of theopenings will allow a preferential fluid flow through the at least oneside opening because fluid will preferentially flow through the largeropening, with the least resistance.

In various embodiments, the at least one side opening may include oneopening in a side wall of the lumen of the catheter body, multiplesmaller spaced-apart openings in the lumen, a combination of multiplesmaller openings and one larger opening, and the like. Generally, the atleast one side opening may have any suitable configuration for infusingan agent and/or aspiration clot and fluid.

In other embodiments, the apparatus allows for preferential fluid flowthrough the at least one side opening by further including a flowresistor between the distal-end opening and the at least one sideopening for inhibiting fluid flow through the at least one lumen.Generally, the flow resistor may comprise any mechanism for inhibitingfluid flow through the at least one lumen such that fluid flow inaspiration and/or infusion occurs preferentially through the at leastone side opening. For example, in one embodiment, the flow resistorallows fluid flow (either infusion, aspiration or both) through thedistal-end opening at a rate of between about 0.1% and about 20% of thetotal fluid flow, and preferably between about 1% and about 5% of thetotal flow. Thus, fluid flow through the at least one side opening wouldaccount for between about 80% and about 99.9% of the fluid flow, andpreferably between about 95% and about 99% of the total flow.

Generally, the optional flow resistor disposed between the distal-endopening and the at least one side opening may have any of a number ofsuitable configurations for inhibiting flow through the at least onelumen to allow preferential flow through the at least one side opening.In one embodiment, the flow resistor comprises a cylindrical materialwith at least one channel. Such a flow resistor may be made from anysuitable material, such as a silicone-based material. Typically, thecylindrical material will have an outer diameter equal to the innerdiameter of the at least one lumen. The at least one channel through thecylindrical material may have any of a number of differentconfigurations in various embodiments of the invention. For example, inone embodiment the channel comprises a cylindrical hole having an innerdiameter sufficient to allow passage of a guidewire. The same hole mayalso allow passage of fluid. In another embodiment, the at least onechannel comprises one or more flexible slits to allow passage of theguidewire and fluid. In yet another embodiment, the at least one channelcomprises a valve for allowing passage of the guidewire and one or moreholes for allowing passage of fluid. Generally, any suitableconfiguration for the cylindrical material and the at least one channelmay be used to inhibit flow of fluid through the lumen distal to theflow resistor.

In another embodiment, the flow resistor comprises a membrane with atleast one aperture. In yet another embodiment, the flow resistorcomprises a ball valve for partially blocking flow of fluid through theat least one lumen, the ball valve having at least one channel, a ball,and a widened area within the channel into which the ball may fall toallow passage of a guidewire through the channel. In yet anotherembodiment, the flow resistor comprises a compliant membrane coupled tothe at least one lumen, the compliant membrane communicating with aninflation lumen, the inflation lumen communicating with an inflationport. Inflation via the inflation port and inflation lumen moves thecompliant membrane to partially or wholly block fluid flow through theat least one lumen of the catheter body. Such an inflation lumen may beseparate from or in communication with an inflation lumen for anexpandable body on the catheter body.

Whether a particular embodiment of the present invention uses differentcross-sectional areas of the distal-end opening and the at least oneside opening, an optional flow resistor, a combination thereof, or someother suitable means, invariably a preferential fluid flow is allowedthrough the at least one side opening. Such a preferential flowgenerally allows aspiration and/or infusion to be concentrated at a clotsite or treatment site adjacent the at least one side opening. At thesame time, some aspiration and/or infusion still typically occursthrough the distal-end opening, which may be advantageous in variousprocedures, for example where some infusion of a thrombolytic agent at alocation distal to the clot is desired.

Some embodiments of the present invention further include a mechanicalagitator near the distal end of the catheter body for mechanicallyagitating clot over the length of the blood vessel. The mechanicalagitator may have a wide variety of specific configurations. Usually,the mechanical agitator will comprise a radially expansible agitatorwhich is rotatable and/or axially translatable relative to the catheterbody. In one embodiment, the radially expansible agitator will beself-expanding, e.g., it may comprise a resilient element which may beradially constrained to have a low profile (small diameter) and may befreed from radial constraint to have an enlarged profile (largediameter) with a non-linear geometry. Typically, radial constraint canbe provided by a sleeve or sheath which may be axially advanced andretracted relative to the catheter body to cover and uncover theradially expansible agitator. In this way, the catheter can beintroduced to a target site within the vasculature with the expansibleagitator covered (and thus radially constrained). After the desiredtarget site is reached, the sheath or sleeve can be axially retracted torelease the radially expansible agitator so that it expands to engagethe clot in the blood vessel. The agitator may then be rotated and/oraxially translated to engage and disrupt the clot in combination withthe release of a thrombolytic agent, as described in more detail below.Such rotation, oscillation, and/or translation will usually beaccomplished using a motor drive unit operatively connected to theagitator, but could in some instances be performed manually in whole orin part.

In an alternative embodiment, the radially expansible agitator maycomprise a resilient element which can be axially shortened to assume anenlarged profile having a non-linear geometry. For example, aself-expanding resilient element may be straightened (tensioned) byinitially positioning a rod or stylet therein in order to lengthen theelement and cause it to straighten to a low profile diameter. Theagitator may then be expanded by retracting the rod or stylet to releasethe agitator from tension and permit the agitator to radially expand asa result of the agitator's inherent spring force. Alternatively, theagitator may be formed to have a generally straight, low profileconfiguration and be actively caused to radially expand by pulling on arod or wire to cause axial shortening.

In all cases, the agitator may have a variety of specific geometries,such as a helical geometry, a spiral geometry, a serpentine geometry, azig-zag geometry, an alternating helix geometry (i.e., two or morehelical geometries in tandem where successive helixes are wound inopposite directions), and/or a variety of other random geometries. Thegeometries will be such that the resilient element can engage againstand penetrate into the clot within a blood vessel as the resilientelement is radially expanded. As the resilient element is thereafterrotated and/or axially translated, the element will then mechanicallyengage and disrupt the clot. By simultaneously introducing thethrombolytic agent directly to the region which is being mechanicallyengaged by the agitator, disruption and dissolution of the clot issignificantly enhanced.

In other embodiments of the invention, an agent such as a thrombolyticagent may be distributed at the luminal length of the blood vessel by anagent distributing means. In some embodiments, such distributing meanswill comprise a porous sheath or other perforate or foramenous structurewhich may be disposed over a radially expansible agitator. The poroussheath may be a thin fabric having a generally uniform porosity alongits length. Alternatively, the sheath could be an impermeable membranehaving a plurality of holes or ports formed along its length to permitthe release of a thrombolytic agent. A wide variety of other perforateor porous structures will also be available. For example, the sheathcould comprise a coil having a plurality of successive turns, wherebending of the coil causes the turns to separate, creating spaces orapertures for the release of the thrombolytic agent. It would also bepossible to form the sheath from an elastic material having pores whichare generally closed but which open when the elastic material istensioned, either by stretching (e.g., due to internal pressurizationwith the thrombolytic agent) or by deforming the elastic sheath materialas the sheath is deformed into its non-linear geometry.

In embodiments of the invention which include a mechanical agitator, thesheath may be able to release the thrombolytic agent along substantiallythe entire length of the agitator which is in contact with the clot tobe disrupted. In this way, the thrombolytic agent will be released atthe point of mechanical agitation, resulting in both improveddistribution of the thrombolytic agent into the clot as well as improveddisruption and dissolution of the clot. Usually, the porous sheath willbe formed as a relatively closely fitting sleeve over the resilientelement, e.g., so that the sheath assumes the same non-linear geometryas the resilient element. Alternatively, however, the sheath may beformed to have larger diameter, e.g., a diameter approaching the luminaldiameter of the blood vessel being treated. In the latter case, thethrombolytic agent may be distributed over the entire region of the clotwhile the agitator presses the sheath into the clot to enhanceintroduction of the thrombolytic agent and dissolution of the clot. Inboth cases, the sheath may be elastic, i.e., expansible in response topressure of thrombolytic agent, or inelastic. Alternatively, the sheathcould be a composite of an elastic fabric or membrane reinforced with agrid or network of elastic or inelastic ribs or other reinforcementmembers.

In an alternative embodiment, the agitator may be configured to directlydeliver the thrombolytic agent into the clot as the agitator is beingdriven. For example, when the agitator is in the form of a non-linearelement, the element may be formed as a tube having a thrombolytic agentdelivery lumen therein. The tube may then be provided with agentdelivery ports and/or porous regions to permit the generally uniformrelease of the thrombolytic agent over the length of the element whichis contact with the clot. In this way, the thrombolytic agent may bedelivered directly into the clot and dissolution enhanced without theneed to provide for a separate thrombolytic agent delivery sheath.

Optionally, the clot disruption and dissolution apparatus of the presentinvention may further comprise means for isolating at least a distal endof the catheter body to reduce blood flow through the region beingtreated by the catheter. For example, at least a single balloon may beprovided on the catheter body distally or proximally of the agitator andthrombolytic agent distribution means on the catheter. When only asingle balloon is used for isolation, it will preferably be on the sideof the thrombolytic agent distribution means which is downstream fromthe region being treated. In this way, the isolation balloon willinhibit the loss of the thrombolytic agent as well as the release ofemboli downstream. Preferably, isolation means will be provided both onthe distal end proximal sides of the agitator and thrombolytic agentdistributing means. Typically, the isolation means will comprise a pairof axially spaced-apart balloons disposed on the catheter body. Furtheroptionally, one of the balloons may be disposed on a separate,telescoping portion of the catheter body in order to permit lengthadjustment of the region to be isolated. Alternatively, a variety ofother isolation means, such as deployable flanges, malecot structures,expansible braids, and the like, could also be employed.

In the apparatus of the present invention which employ both an agitatorand a sheath, the agitator may optionally be replaceable within thesheath and/or axially translatable within the sheath. Still furtheroptionally, the sheath itself may be introduceable over a guidewire,either with or without the agitator being in place within the sheath.Thus, the apparatus may provide for the free interchangeability of twoor more agitators and at least one guidewire for initially placing thesheath. It will be appreciated that such replaceability provides greatadaptability of the systems of the present invention. For example, thesheath could be introduced to a treatment site within the vasculatureover a conventional guidewire or a guidewire with a balloon and/orfilter on it. After withdrawing the guidewire, a first agitator could beintroduced to within the sheath and the target site treated by bothagitation and release of the thrombolytic agent. It would then bepossible to reposition the agitator within the sheath to treat adifferent region of the vasculature. Alternatively or additionally, itwould be possible to remove the first agitator and replace it with asecond agitator selected to better treat the region and/or to providefor a subsequent treatment step of that region.

The catheters of the present invention may optionally be provided withlumen(s) for introduction over a guidewire or a guidewire with a balloonand/or filter on it. For example, the catheter (or a sheath componentthereof) may be introduced over a guidewire using a central lumen whichalso receives the agitator. Alternatively, separate guidewire lumen(s)could be provided on the sheath or elsewhere, e.g., a short guidewirelumen could be provided near the distal tip of the sheath beyond thenon-linear region defined by the agitator. Such a short lumen wouldavoid interference with the agitator. Inflation of a guidewire balloondistal of the catheter may help isolate the region of the vessel fromblood flow. A variety of specific designs will be available.

The apparatus of the present invention will still further be availableof systems comprising at least one sheath together with two or moreagitators which are removably replaceable within the sheath. Suchsystems allow for treatment of different diseases and different regionsof the vasculature. The treating physician can either choose the initialcombination which is best for a particular disease, or may begintreatment with one combination of sheath and agitator and continuetreatment thereafter with another combination of sheath and agitator.

In another apparatus aspect, the invention provides an apparatus fordisrupting clot over a target region of a blood vessel. The apparatuscomprises a catheter body having a proximal end and a distal end. Anagitator is disposed near the distal end for mechanically agitating clotover the target region. A port near the distal end is in fluidcommunication with an agent supply source for distributing an agentalong the target region.

In many embodiments, the agent will comprise a thrombolytic agent, whichmay provide an enzymatic action to break down fibrin clot matrix. Avariety of other agents may also be used, including group IIb/IIIaInhibitors (typically to inhibit fibrinogen binding site of plateletmembrane, other anti-platelet agents, anti-thrombin agents and agentsdirected toward prevention of restenosis (which may inhibit coagulationand/or inhibit restenosis by decreasing smooth muscle proliferation andmigration), gene therapeutic agents (currently under development, oftenfor preventing restenosis and promoting angiogenesis), chemotherapeuticagents (generally designed to treat malignancies) imaging media, and/orother potential agents.

The present invention still further provides a method for disruptingclot over a luminal length of a blood vessel. The method includes firstpositioning a catheter body with at least one lumen at a location withinthe luminal length of the blood vessel. The at least one lumen of thecatheter body has a distal-end opening and at least one side opening.The method then includes infusing an agent through the distal-endopening and the at least one side opening, where the infusionpredominantly occurs through the at least one side opening.

Optionally, methods of the present invention also include mechanicallyagitating the clot over the luminal length of the blood vessel. In someembodiments, the methods comprise infusing the thrombolytic agent in adistributed pattern over the treated length. By “distributed pattern,”it is meant that the thrombolytic agent is not simply released into thetreatment region but rather that it is introduced directly into the clotat the interface region where the clot is being mechanically agitated.For example, in the case where mechanical agitation is achieved using anon-linear element, the thrombolytic agent will be delivered at pointswhich are distributed over the non-linear element so that they enter theclot at the “point of attack” described above in connection with theapparatus. The thrombolytic agent can be delivered using a porous sheathwhich is disposed over the non-linear agent in a sleeve-like manner.Alternatively, the thrombolytic agent can be delivered through a lumenwithin the non-linear agent and released through a plurality of ports orporous regions in the non-linear element. In both cases, the ability todeliver the thrombolytic agent directly into the clot as it is beingmechanically penetrated by the element will enhance distribution of thethrombolytic agent within the clot and improve the efficiency of clotdissolution as well as decrease the particle size reduction achieved ina given period of time.

In specific aspects, the methods of the present invention are used totreat predetermined luminal lengths, typically having a length of atleast 5 cm, usually at least 100 cm, and most usually in the range from10 cm to 50 cm. When the blood vessel is a vein, the targeted regionsmay be selected from the group consisting of vena cava, iliac vein,femoral vein, popliteal vein, common iliac vein, external iliac vein,brachial vein, and subclavian vein. When the target blood vessel is anartery, the preferred arteries are the internal iliac artery, externaliliac artery, popliteal artery, coronary arteries, superficial femoralartery, and the brachial artery.

Preferably, mechanical agitation comprises rotating and/or axiallytranslating a radially expansible agitator within the blood vessel andagainst the clot. The exemplary agitators have been described above.Optionally, the mechanical and agitation and thrombolytic agent deliverymay be performed within isolated regions of the vasculature, typicallyprovided by inflating one or more balloons within the vasculature ateither side of the treatment region. Most preferably, a pair of axiallyspaced-apart balloons will be disposed on either side of the treatmentregion to provide isolation, both to maintain higher thrombolytic agentconcentrations within the region and to inhibit the release ofthrombotic clot prior to sufficient dissolution of the clot.

The methods of the present invention allow for a wide variety ofparticular treatment protocols. For example, the agitator may be drivenat different and/or variable speeds. Typically, the agitators will berotated and/or oscillated at speeds in the range from 0 rpm to 50,000rpm, preferably from 50 rpm to 5,000 rpm. The speeds may be set and/oradjusted at a wide variety of particular rotational speeds within theseranges. In some cases, the direction of the rotation can be reversedduring the course of the procedure. It will further be possible toaxially advance or retract the agitator, optionally within a sheath,during the course of treatment to enhance the disruption of the clot andintroduction of the thrombolytic into the clot. Still furtheradditionally, it will be possible to vary the width or diameter of theagitator during the course of treatment to enhance disruption.

In general, infusing the agent predominantly through the at least oneside opening is accomplished via a larger cross-sectional area of theside opening compared to the distal-end opening, via a flow resistor, orby any other suitable means, as described in greater detail above inrelation to apparatus of the invention. In some embodiments, one or moreagents may be infused through the lumen of the catheter body and clotand/or fluid may be aspirated through the same lumen. In other methods,infusion and aspiration may be performed through separate lumens. Instill other embodiments, infusion is performed through a sheathsurrounding the catheter body and aspiration is performed through thelumen of the catheter body. In other methods, infusion is through thelumen and aspiration is through the sheath. In some of the embodiments,a guidewire may be left in position in one lumen during infusion,aspiration or both.

As just suggested, the treatment methods of the present invention mayoptionally comprise aspiration of the disrupted clot from the treatmentsite. Aspiration may be accomplished using a lumen or lumens within thesheath and/or agitator to withdraw the disrupted clot. Optionally,mechanical means, such as an Archimedes screw or other pump, may beincorporated into the catheter to enhance the aspiration and removal ofthe disrupted clot. In other embodiments, such a pump may be mounted toa separate structure, such as to a sheath removably disposed over thecatheter, an inner structure removably disposed within a lumen of thecatheter, or the like. Still further embodiments may rely on anaspiration means which remains outside the patient, such as a syringe,vacuum container, or the like.

Still further optionally, the disrupted clot and other fluid orfluidized materials within the treatment region may be recirculated toenhance breakup of the clot and activity of thrombolytic agent. Forexample, pairs of spaced-apart ports or apertures on the sheath may beused to draw in the material within the treatment region and expel thatmaterial at a different point within the treatment region. Suchrecirculation may significantly enhance the thrombolytic activity anddecrease the treatment time.

As a still further option, it is possible to periodically orcontinuously introduce blood into the treatment region. tPA acts onplasminogen within the vasculature to breakup thrombus. If the treatmentregion of the present invention is isolated, it may be beneficial tointroduce fresh blood containing plasma in order to enhance the activityof the thrombolytic agent, particularly tPA. Most simply, fresh bloodcould be introduced by periodically opening an isolation balloon whichisolates the treatment region.

The methods of the present invention can rely on two or more of thetreatment catheters to be used simultaneously. For example, in thetreatment of arterio-venous grafts, it is possible to introduce twotreatment catheters according to the present invention, each of whichhas a balloon or other occlusion device at its distal end, to an A-Vgraft at a point near its middle. By introducing the two treatmentcatheters in opposite directions, the graft can be isolated very closeto the points at which it is anastomosed to the natural vasculature.After such isolation is achieved, the interior of the A-V graft can thenbe cleaned out according to the methods of the present invention, andpreferably the released clot and thrombus may be withdrawn through anaccess sheath to the A-V graft.

The present invention still further comprises kits, including a catheterhaving an agitator in a thrombolytic agent delivery means. The kits willfurther include instructions for use according to any of the methods setforth above. In addition to the catheter and the instructions for use,the kits will usually further comprise packaging, such a box, pouch,tray, tube, bag, or the like, which holds the catheter and theinstructions for use. Usually the catheter will be maintained sterilelywithin the package, and the instructions for use will be printed on aseparate package insert or piece of paper. Alternatively, theinstructions for use may be printed in whole or in part on a portion ofthe packaging.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of clot disruption apparatus constructed inaccordance with the principles of the present invention.

FIG. 2 is a detailed view of the distal end of the clot disruptionapparatus of FIG. 1, showing the sheath and agitator components thereof.

FIG. 2A illustrates an aspiration pump which may be integrated into theapparatus of FIG. 1 for aspiration of disrupted clot material.

FIG. 3 illustrates use of the clot disruption apparatus of FIG. 1 intreating a thrombosed region within a blood vessel according to themethods of the present invention.

FIG. 4 illustrates an alternative construction of an agitator useful inthe apparatus of the present invention.

FIG. 5 illustrates a second alternative construction of an agitatoruseful in the apparatus of the present invention.

FIG. 6 illustrates a third alternative construction of an agitatoruseful in the apparatus of the present invention.

FIG. 7 illustrates a fourth configuration of an agitator useful in theapparatus of the present invention.

FIG. 8 illustrates a method and apparatus according to the presentinvention for treating an isolated region of the vasculature.

FIGS. 9, 9A and 9B illustrate alternative methods and apparatusaccording to the present invention for treating an isolated region ofthe vasculature.

FIGS. 10A and 10B illustrate yet another alternative embodiment of themethods and apparatus of the present invention for treating an isolatedregion of the vasculature.

FIG. 11 illustrates a still further embodiment of the apparatus andmethods of the present invention for treating an isolated region of thevasculature.

FIG. 12 illustrates a first method for treating an arterio-venous graftaccording to the methods of the present invention.

FIG. 13 illustrates a second method employing a pair of clot disruptioncatheters for treating an arterio-venous graft according to the methodsof the present invention.

FIG. 14 illustrates a kit for performing the methods of the presentinvention, wherein the kit is constructed in accordance with theprinciples of the present invention.

FIG. 15 illustrates a clot disruption apparatus having a sheath and acatheter body, the catheter body having a lumen with a distal-endopening and a side opening according to one embodiment of the presentinvention.

FIG. 16 a illustrates a cross section of the distal end of a clotdisruption apparatus having a cylindrical flow resistor and a commonlumen for infusion and aspiration, according to one embodiment of thepresent invention.

FIGS. 16 b-d illustrate frontal views of various configurations of aflow resistor for a clot disruption apparatus as in FIG. 16 a.

FIG. 17 illustrates a cross section of the distal end of a clotdisruption apparatus having a cylindrical flow resistor and two separatelumens, one for infusion and one for aspiration, according to oneembodiment of the present invention.

FIGS. 18 a-b illustrate a cross section of the distal end of a clotdisruption apparatus having a compliant membrane flow resistor and acommon lumen for infusion and aspiration, according to one embodiment ofthe present invention.

FIG. 19 illustrates a cross section of a ball valve flow resistor whichmay be used in the distal end of a catheter body lumen according to oneembodiment of the present invention.

FIGS. 20 a-g illustrate a method for disrupting a clot according to oneembodiment of the present invention.

FIGS. 21 a-g illustrate a method for disrupting a clot according toanother embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1, a clot disruption apparatus 10 is shown to comprise acatheter body 12, a motor drive unit 14, and a thrombolytic agentdelivery device 16. The motor drive unit 14 is attached to a hub 18 at aproximal end 20 of the catheter body 12. The thrombolytic agent deliverydevice is shown as a syringe which is attached to a side port 22 on hub18 through a conventional tube 24. It will be appreciated that otherthrombolytic agent delivery devices could also be used, such as pumps,gravity bags, and the like. The thrombolytic agent delivered by device16 can be any conventional bioactive agent which is capable ofdisrupting and dissolving clot and thrombus, such as tissue plasminogenactivator (tPA), streptokinase, urokinase, heparin, low molecular weightheparin, and the like. The thrombolytic agents may be delivered throughthe delivery device 16 as a bolus, continuously over time, or ascombinations thereof.

Use of the present invention will generally be described with referenceto thrombolytic agents, often those having enzymatic action which breaksdown fibrin clot matrix. In addition to tPA, suitable thrombolyticagents may include Alteplase or Activase™, Tenecteplase, TNK, andTNKase™, all of which are from Genentech, Inc; Anistreplase, a-SK,Eminase™, from Roberts Pharmaceuticals; Reteplase, r-PA, Retavase™, fromCentocor, Inc.; Streptokinase, SK, Streptase™, from AstraZeneca, Inc.;and Abbokinase™, Abbott, Inc. A variety of other agents may also beused, including Group IIb/IIIa Inhibitors which may inhibit fibrinogenbinding site of platelet membrane, such as Abciximab and ReoPro™, fromCentecor, Inc.; Tirofiban and Aggrastat™ from Merck, Inc.; Eptifibatideand Integrelin™ from Cor Therapeutics, Inc.; and other IIb/IIIainhibitors such as Bitistatin and Kistrin, or other anit-platelet agents(such as aspirin).

The invention may also be used with anti-thrombin agents and agentsdirected toward prevention of restenosis to inhibit coagulation and/orinhibit restenosis by decreasing smooth muscle proliferation andmigration, such as Heparin (LMW containing most anticoagulant activity,and also inhibits smooth muscle proliferation and migration),enoxaparine or Lovenox™, dalteparin or Fragmin™, and ardeparin orNormoflo™, Hirudin, Argatroban, PPACK to inhibit thrombin inducedplatelet activation and platelet secretion of PDGF which may beresponsible for smooth muscle proliferation and migration, radioactiveagents (such as for vascular brachytherapy, inhibits smooth muscleproliferation), locally delivered nitrate (nitric oxide, prevents reflexvasoconstriction at site of injury and inhibits activation ofcirculating platelets in order to decrease late luminal narrowing),HA1077 (which inhibits action of cellular protein kinases andsequestration of cellular calcium, acts as vasodilator, and may inhibitsmooth muscle proliferation), and other anti-restenosis agents (such ascalcium antagonists, angiotensin converting enzyme inhibitor,anti-inflammatory agents, steroidal agents, anti-mitotic agents, HMG CoAreductase inhibitors, colchicine, angiopeptin, cytoclasin B (inhibitsactin polymerization and muscle cell motility.

In still further alternatives, the invention may be used with genetherapeutic agents, new agents and/or agents which under development forpreventing restenosis and promoting angiogenesis. Such agents may bedelivered via plasmid vectors or by viral vectors. Examples includegenes relating to: VEGF, C-myb, FGF, transforming growth factor b,endothelial growth factor, protooncogenes such as C-myc, C-myg, CDC-2,and PCNA.

Still further alternative agents may be used with the devices andmethods of the present invention, including chemotherapeutic agents(agents used to treat malignancies, such as adriamycin or Doxorubicin™),imaging media (including contrast media and radioactively labeledagents), plasminogen additive (as an adjunct to thrombolytic therapy),immunosuppressive agents, and other potential agents.

A motor drive unit 14 includes a sliding switch 26 which controls therotational speed of the motor and a sliding collar 28 which controls theaxial position of an agitator 30 within a sheath 32 of the catheter body12 (FIG. 2). A non-linear region 34 of the catheter body 12 is definedby the agitator 30 within the sheath 32. By axially translating theagitator 30 using the collar 28, the non-linear region of the catheterbody can be moved in a proximal or distal direction along the catheterbody. The motor drive unit will be capable of rotating the agitator 30within the sheath 32 at the rotational rates set forth hereinabove.Additionally, the motor drive unit 14 may be adapted in othercircumstances to oscillate the agitator, axially reciprocate theagitator, or provide for other mechanical movements of the agitatorwhich can cause or contribute to clot disruption according to themethods of the present invention.

Referring now in particular to FIG. 2, the sheath 32 comprises a tubularbody formed from a polymeric material, a fabric, or other material, andincludes a plurality of fluid distribution ports 40 along its length. Asillustrated, the fluid distribution ports 40 are only formed over aportion of the length of the sheath. It will also be possible to formthe ports over the length which is greater than the non-linear regiondefined by the agitator 30. The agitator 30 is shown to be a shorthelical section having one complete turn. Other geometries will includetwo-dimensional geometries, such as single humps, S-shapes, zig-zagpatterns, and the like. Suitable three-dimensional geometries includehelical geometries, alternating helixes, spirals, and the like. In allcases, as the non-linear region of the agitator is rotated within thesheath, the sheath will be caused to trace a three-dimensional envelopewithin the blood vessel being treated. Usually, the agitator 30 willforce the sheath into engagement with clot or thrombus within the bloodvessel, and the thrombolytic agent will be released through the ports 40as the sheath is being engaged by the agitator. In this way, thethrombolytic agent is introduced directly into the clot or thrombus asthe clot is being mechanically disrupted. This combination of mechanicaland chemical dissolution of the clot is every effective and can reducethe clot disruption time significantly when compared to otherthrombolytic techniques.

As will be described in more detail below, the apparatus of FIGS. 1 and2 may be used with a variety of additional structures to help remove thedisrupted clot material. Optionally, a simple external vacuum source 15may be coupled to the motor drive unit 14 to draw material proximallythrough an aspiration lumen of the catheter body. A wide variety ofaspiration sources may be used, including a simple locking syringe.

In some embodiments, a pump element 29 shown in FIG. 2A may be disposedwithin the aspiration lumen to help pump the clot material proximallythrough the catheter body. As described in detail in co-pendingapplication Ser. No. 09/454,517, filed on Dec. 6, 1999, the fulldisclosure of which is incorporated herein by reference, pump element 29may comprise a tubular body 31 having a lumen 33 therein and a helicalelement 35 disposed thereover. When pump element 29 rotates within anaspiration lumen in catheter body 12 (or alternatively, in a sheathsurrounding the catheter body or a separate aspiration catheterextending along catheter body 12), material can be urged axially (eitherproximally or distally, depending on the direction of rotation). Suchpumps are sometimes referred to as an “Archimede's screw.” Pump element29 may be formed from at least a portion of a shaft drivingly couplingagitator 30 to the motor drive unit, or may comprise a separately drivenstructure.

In some embodiments, such as when the region of the blood vessel to betreated will be isolated both proximally and distally, it may beadvantageous to maintain a substantially constant fluid volume withinthe region of the blood vessel. As described in detail in applicationSer. No. 09/751,216, filed on Dec. 29, 2000, the full disclosure ofwhich is incorporated herein by reference, an at least roughly equalquantity of fluid (including the therapeutic agent) may be introducedinto the vessel as the total volume aspirated from the vessel byfiltering the aspirated fluid from the solid clot material and byreintroducing the filtered fluid back into the vessel.

Use of the clot disruption apparatus 10 of FIGS. 1 and 2 is illustratedin FIG. 3. The non-linear region 34 of the catheter body 12 ispositioned within a treatment region TR of the blood vessel BV beingtreated. Once in place, the agitator 30 is rotated, as indicated byarrow 42 and the non-linear region sweeps an ovoid volume within thetreatment region TR, disrupting and dissolving clot as the thrombolyticagent is released from the ports 40. Alternatively or additionally, thenon-linear region 34 could be rotated in the direction opposite to arrow42, could be rotationally oscillated, axially oscillated, orcombinations thereof.

As described in the Summary above, the agitator may operate togetherwith a thrombolytic agent delivery sheath (as illustrated in FIGS. 1-3)or may alternatively be configured to deliver the thrombolytic agentdirectly, e.g., through a lumen in the agitator as illustrated in FIG.4. Agitator 50 of FIG. 4 includes a non-linear region 52 which consistsof a simple, two-dimensional curve which forms a hump in the agitator.The non-linear region has a plurality of thrombolytic agent deliveryports 54 formed over its length so that the non-linear region 52 canrelease the thrombolytic agent directly into the thrombus being treatedas the agitator is rotated. In a first instance, the agitator 50 may beformed from a resilient material with the non-linear curve being formedso that it assumes the curve when released from constraint. The agitator50 could then be delivered to a target site within a blood vessel withina separate delivery sheath. When the agitator 50 is advanced from thesheath, it will assume the non-linear geometry illustrated in FIG. 4.Alternatively, as shown in FIG. 5, the sheath 50 can be delivered withan internal stiffener 56 which tensions the agitator so that thenon-linear region 52 (shown in broken line) is straightened (shown infull line) when the stiffener 56 is axially advanced within the lumen 60thereof. It will also be possible to configure the agitator 50 so thatit assumes a straight configuration when free from axial tension andcompression. When under compression, however, the agitator will beformed so that it will collapse and assume the non-linear configuration52 shown in FIG. 4. The agitator 50 could also be formed from heatmemory alloys which are straight at room temperature but which assumetheir non-linear configuration when introduced to the body temperature.By introducing such catheters in a cooled environment, e.g., whilebathed in cooled saline, they can reach their target site in astraightened configuration and thereafter assume the non-linearconfiguration as they return to body temperature.

In addition to perforate structures for release of the thrombolyticagent, as shown in FIGS. 4 and 5, an agitator 62 having a sheath 63formed as a coiled structure 64, as shown in FIG. 6, may also be used.The coil can be configured to have a non-linear region 64, such as asimple curve, or any of the other geometries discussed and illustratedabove. When in a linear configuration, adjacent turns of the coil willlie close together and form a generally fluid-tight seal. When in thenon-linear configuration illustrated in FIG. 6, however, adjacent turnsof the coil will move apart to form a plurality of spaces or gaps 66 atregions where the coil structure turns. These gaps 66 connect to releasethe thrombolytic agent as the agitator is rotated. Sheath 63 may beinduced into its linear configuration using a stiffening member 68, asillustrated.

An agitator 70 having an alternating helical geometry is illustrated inFIG. 7. Non-linear region 72 of the agitator 70 comprises a firsthelical section 74 and a second helical section 76. The helical section74 and 76 are wound in opposite directions so that when the agitator 70is rotated in the direction of arrow 78, materials within the bloodvessel lumen will be urged to move in the direction of arrows 80 towarda central region of the agitator 70. In this way, the agitator 70creates its own isolation region within the blood vessel. The materialsbeing disrupted and dissolved are constantly urged toward the center, toinhibit release from the treatment region. Over time, the materials willbecome completely broken down, or at least sufficiently broken down sothat their release will not present significant risk to the patient.

Agitator 70 can comprise a sheath and separate agitator (similar to thedesign of FIGS. 1-3) or may comprise a monolithic structure where thethrombolytic agent is released directly through perforations or otherdiscontinuities in the agitator wall. In some embodiments of the method,a simple bend in a guidewire may be used to mechanically agitate clotmaterial and a therapeutic agent within an isolated region of thevessel, even using manual rotation of the guidewire.

Referring now to FIG. 8, the clock disruption catheters of the presentinvention may be advantageously combined with balloon or other isolationmeans. Clot disruption catheter 90 comprises a catheter body 92 having adistal isolation balloon 94 and proximal isolation balloon 96 formedthereon. A non-linear region 98 of the catheter body 92 is formedbetween the isolation balloons 94 and 96. Conveniently, the isolationballoons 94 and 96 may be formed directly over a sheath 100 whichremains stationary while an agitator 102 is rotated, oscillated, and/oraxially translated therein. The balloons 94 and 96 may be inflatedthrough a common or separate inflation lumens formed within the sheath92. The inflation lumens (not shown) will be isolated from thethrombolytic agent delivery lumen. Thrombolytic agent is deliveredthrough ports 104 formed in the sheath between the isolation balloons 94and 96. Radiopaque markers 106 are positioned at either end of thetreatment region, typically within the isolation balloons 94 and 96. Thestructure of catheter 90 is advantageous in that it will completelycontain the thrombolytic agent and all disrupted clot between theisolation balloons 94 and 96. Optionally, aspiration means can beprovided, e.g., through a fourth lumen within the sheath 100, in orderto withdraw materials from the treatment region.

Referring now to FIG. 9, a catheter 120 having means for recirculatingthe thrombolytic agent and other materials through a treatment region isillustrated. Catheter 120 comprises spaced-apart isolation balloons 122and 124. The catheter is generally similar to that described above withreference to FIG. 8. Catheter 120, however, further includes a pump,typically in the form of an Archimedes screw 126 disposed between afirst port 128 and a second port 130 on the body of catheter 120.Rotation of the Archimedes screw will draw material into the port 130and expel the material from port 128. Such recirculation enhances theagitation and thrombolytic activity of the thrombolytic agent which isreleased through the ports as generally described above with respect toall earlier embodiments.

The catheters of the present invention can also be provided with bloodbypass and perfusion lumens for a variety of purposes. For example, asillustrated in FIG. 9A, a catheter 131 having spaced-apart balloons 132and 133 can have an inlet port upstream of proximal balloon 132 and anoutlet port 135 between the balloons 132 and 133. In this way, freshblood can be introduced into the otherwise isolated region between theballoons to enhance the thrombolytic activity of the tPA or otherthrombolytic agent being released by the catheter.

As illustrated in FIG. 9B, catheter 131 could also be provided with aninlet port 136 upstream of proximal balloon 132 and an outlet port 137downstream of distal balloon 133 in order to provide perfusiondownstream of the region being treated. In both FIGS. 9A and 9B, theinlet and outlet ports will be connected by internal lumen(s) which arepreferably isolated from the lumen(s) which are supplying thethrombolytic agent.

FIGS. 10A and 10B illustrate a catheter 140 comprising catheter body 142and an inner catheter shaft 144. A proximal isolation balloon 146 isformed at the distal end of the catheter body 142. The distal isolationballoon 148 is formed at the distal end of the inner catheter body 144.Thrombolytic agent distribution ports 150 are formed over a non-linearregion 152 of the inner catheter body 144. In this way, the length ofthe non-linear region and thrombolytic agent release region 152 can beadjusted by axially extending or retracting the inner catheter member144 relative to the catheter body 142. In particular, balloon 146 oncatheter body 142 may be anchored at a proximal end of a desiredtreatment region. The distal isolation balloon 148 may then be extendedby a desired distance from the distal tip of the catheter body 142 tocreate an isolated treatment region therebetween (with both balloonsbeing inflated). The non-linear region 152 may then be rotated withthrombolytic agent released in order to treat the clot and thrombusbetween the balloons. Optionally, the released emboli can be aspiratedthrough the distal end of the catheter body 142 and withdrawn from thetreatment region. After a first portion of the treatment region isremediated, the distal isolation balloon 148 can be deflated, and thedistal end of the inner catheter member 144 extended further distally.This creates a new treatment region, which region can be treated in themanner just described, Two, three, or more such iterations can beperformed successively in order to treat disseminated disease within ablood vessel lumen.

Referring now to FIG. 11, a clot disruption catheter 160 comprisingexpansible filter elements 162 and 164 is illustrated. The filterelements 162 and 164 provide partial isolation of a treatment regiontherebetween. The filter elements will capture emboli, but generallypermit blood flow through the region. Catheter 160 further includes anon-linear region 168 and thrombolytic agent delivery ports 170,generally as described for previous embodiments. The non-linear region168 may be rotated in order to effect clot disruption and dissolution,again generally as described above. Filter elements 162 and 164 willserve to capture at least most of the clot which is released.

Referring now to FIG. 12, a clot disruption catheter, such as catheter10 may be used to treat an arterio-venous graft AVG. The catheter 10 isintroduced through a delivery sheath 180 so that non-linear region 34lies within a highly thrombosed region of the graft AVG. The catheter isrotated and optionally axially translated, generally as described above.Thrombolytic agent can be released through the delivery device 16. Thedelivery sheath 180 can be adapted to provide for aspiration through asyringe 182 in order to retrieve at least a portion of the clot which isreleased from the graft.

Two or more of the clot disruption catheters of the present inventionmay be used at the same time to treat a diseased region (or more thanone diseased regions) within the patient. Referring to FIG. 13, anarterio-venous graft AVG can be treated with a pair of identicalcatheters 200, each of which includes a distal isolation balloon 202 butwhich does not include any proximal or other isolation balloons. Eachcatheter 200 further includes a non-linear region 204 defined by anagitator 206 within an exterior sheath 208. The AVG can be treated bypositioning each distal isolation balloon 202 at a position close to theanastomotic junction with the associated artery and vein. The catheters200 are introduced through a common delivery sheath 220, and theagitators 206 may be axially translated (repositioned) within the sheathin order to treat substantially the entire length between the distalisolation balloon 202 and the delivery sheath 220. Thrombolytic agentwill be delivered generally as described above in other embodiments.Similarly, the non-linear regions 204 will be rotated in order to effectclot disruption and enhance thrombolytic agent activity. After treatmentis completed, both catheters may be withdrawn through the sheath 220 andthe AVG graft closed in the conventional manner.

The present invention still further comprises kits including at leastsome of the system components of the apparatus of the present inventiondescribed herein together with packaging, instructions for use, and/orother conventional kit components. For example, as illustrated in FIG.14, a kit 240 may comprise at least a catheter 242, instructions for use244, and packaging 246. The catheter 242 can be any of the cathetersdescribed hereinabove, and the instructions for use 244 may set forthany of the methods of the present invention described hereinabove. Thecatheter 242 will be packaged within the packaging 246, typically in asterile fashion. Conventional medical device packaging may be used, suchas a pouch, tube, tray, box, or the like. The instructions for use maybe printed on a separate package insert, or may be printed in whole orin part on the packaging. Other kit components, such as a motor driveunit 248, an additional agitator 250 (optionally including two or moreadditional agitators having different geometries), may also be added.

Referring now to FIG. 15, another embodiment of a clot disruptionapparatus 260 suitably includes a catheter body 262 having a proximalend, a distal end, and at least one lumen (not visible in FIG. 15). Thelumen has at least one side opening 266 and a distal-end opening 268,both at or near the distal end of catheter body 262. Catheter body 262typically further includes a first radially expandable body 270.Optionally, in various embodiments, catheter body 262 may furtherinclude a flow resistor (not shown), a second radially expandable body274 and/or a plurality of spaced-apart smaller openings 272 into thelumen. Apparatus 260 may optionally further include a sheath 276 with aluminal opening 278 for infusing and/or aspirating fluids, an aspirationmechanism 282 and/or an infusion mechanism 280. Although not shown inFIG. 15, apparatus 260 is typically positioned within a luminal lengthof a blood vessel 264 by passing apparatus 260 over a guidewire. In someembodiments, a guidewire is included as part of apparatus 260 or as partof a kit including apparatus 260. Apparatus 260 may optionally furtherinclude one or more of the elements described with reference to variousembodiments set forth above, such as a mechanical agitator, anaspiration device, and/or the like.

Generally, as described in detail above, clot disruption apparatus 260will be positioned in a luminal length of blood vessel 264 such that oneor more agents may be infused at an area of clot. Optionally, agitatingmeans may be used to agitate the clot and aspiration means may be usedto aspirate clot and/or fluid containing clot particles, blood, infusateand the like. In one embodiment, infusion is performed through sheath276 and aspiration is performed through side opening 266 and distal-endopening 268 of the lumen of catheter body 262. Such functionality isdesignated by the hollow arrows (infusion) and the dark arrows(aspiration) in FIG. 15. Conversely, infusion may alternatively beperformed through side opening 266 and distal end opening 268 andaspiration may be performed through sheath 276. In another embodiment,aspiration and/or infusion may additionally occur through spaced-apartopenings 272. In one embodiment, infusion and aspiration are performedsimultaneously, while in others infusion occurs before aspiration. Againin various embodiments, infusion and/or aspiration may be performed withfirst radially expandable body 270 expanded, with second radiallyexpandable body 274 expanded, with neither expanded, or in some caseswith both expanded.

In other embodiments of the present invention, described in furtherdetail below, apparatus 260 does not include a similar sheath 276. Insome of these embodiments, infusion, aspiration and passage of aguidewire are all performed through a common lument in catheter body262. In other embodiments, separate lumens in catheter body 262 are usedfor separate functions, for example one lumen may be for infusion andanother lumen may be for aspiration and passage of a guidewire.Alternatively, one lumen may be used for infusion and guidewire passageand another may be used for aspiration. In various of these embodiments,infusion, aspiration or both may be performed with a guidewire in placewithin apparatus 260, for example with a guidewire tip protrudingthrough distal-end opening 268.

Generally, apparatus 260 enables fluid flow, as in aspiration and/orinfusion, to occur preferentially through the at least one side opening266 while still allowing minimal aspiration and/or infusion throughdistal-end opening 268. Such preferential fluid flow is accomplishedthrough any of a number of suitable means. In many embodiments, forexample, the cross-sectional area of distal-end opening 268 issignificantly smaller than the cross-sectional area of at least one sideopening 266. For instance, in one embodiment the cross-sectional area ofdistal-end opening 268 is between about 0.1% and about 20%, and morepreferably between about 1% and about 5%, of the cross-sectional area ofat least one side opening 266. In various embodiments, this differencein cross-sectional area will be sufficient to provide preferential fluidflow through at least one side opening 266.

In other embodiments, apparatus 260 further includes a flow resistor(not shown in FIG. 15) between at least one side opening 266 and distalend opening 268 for resisting fluid flow through at least one lumen incatheter body 262. Flow resistor typically acts in conjunction with adifference in cross-sectional areas between distal-end opening 268 andat least one side opening 266 to provide preferential, or predominant,fluid flow through at least one side opening 266.

Referring now to FIG. 16 a, one embodiment of a clot disruptionapparatus distal end 300 suitably includes a catheter body 302 having alumen 304, a flow resistor 310 and a first expandable body 314. Lumen304 further includes a side opening 306 and a distal-end opening 308,and flow resistor 310 is configured generally as a cylindrical memberhaving a cylindrical channel 312. In other embodiments, flow resistor310 may have any other suitable configuration, as will be described morefully below. In one embodiment, for example, flow resistor 310 maycomprise a membrane, disc or the like, having one or more holes, ratherthan a cylinder having a channel. In other embodiments, as describedabove, distal end 300 does not include a flow resistor.

Generally, distal-end opening 308 will have a significantly smallercross-sectional area than side opening 306. For example, in oneembodiment the cross-sectional area of distal-end opening 308 is betweenabout 0.1% and about 20%, and more preferably between about 1% and about5%, of the cross-sectional area of side opening 306. In embodiments ofdistal end 300 including flow resistor 310, channel 312 will typicallyhave a cross-sectional area smaller than distal-end opening. Forexample, in one embodiment, cross-sectional area of channel 312 isbetween about 0.1% and about 8%, and more preferably between about 0.5%and about 4%, of the cross-sectional area of side opening 306. In otherembodiments, the cross-section area of channel 312 may be approximatelyequal to the cross-sectional area of distal-end opening 308. Inembodiments including a membranous or disc-shaped flow resistor, a holeor holes through the membrane or disk will have cross-sectional areassimilar to those just described in relation to cylindrical flow resistor310 and channel 312.

Channel 312 (or channels, or holes, or the like) may have any suitablediameter, configuration or shape for allowing the passage of a guidewirethrough flow resistor 310. Channel 312 also typically allows passage ofsome fluid through flow resistor 310. In some embodiments, minimal fluidflow may occur with a guidewire in place in channel 312. Flow resistor310 does resist flow through lumen 304, however, thus assisting in theprovision of preferential fluid flow through at least one side opening306 relative to distal-end opening 308. In one embodiment, thepercentage of total fluid flow through flow resistor 310 and distal-endopening 308 is between about 0.1% and about 20% of the total fluid flowthrough lumen 304, with the remaining about 80% to about 99.9% flowingthrough side opening 306. More preferably, the percentage of total fluidflow through flow resistor 310 and distal-end opening 308 is betweenabout 1% and 5% of the total fluid, with the remaining about 95% toabout 99% flowing through at least one side opening 306.

Flow resistor 310 may be made of any suitable material and may have anysuitable configuration for allowing passage of a guidewire and forinhibiting fluid flow. In some embodiments, flow resistor 310 is made ofa compliant, silicon-based material. Other materials may be used,however, such as but not limited to plastic, metal, polymer, or acombination thereof. Similarly, flow resistor 310 may have any suitablelength, shape, diameter or configuration. In most embodiments, the outerdiameter of flow resistor 310 will be approximately equal to the innerdiameter of lumen 304, to enhance flow inhibition. Since many diametersof catheter bodies, lumens and the like are contemplated within thescope of the present invention, many possible diameters of flow resistor310 are also contemplated.

Referring now to FIGS. 16 b-d, flow resistor 310 (shown in front view)may suitably include multiple channels, openings, slits, pores, holesapertures, and/or the like, for allowing passage of a guidewire and/orinhibiting fluid flow. In the embodiment shown in FIG. 16 b, forexample, flow resistor 310 includes a guidewire channel 326 and a fluidchannel 328. Such a configuration may be advantageous, for example, wheninfusion or aspiration is desired with a guidewire in place to supportor position catheter body 302. FIG. 16 c shows another embodiment, inwhich flow resistor 310 includes a guidewire channel 324 and multiplefluid channels 322. Of course, in either of the embodiments in FIGS. 16b and 16 c, if a guidewire is not in place within the guidewire channel,fluid may flow through the guidewire channel. In some embodiments, asmentioned above, some fluid flow may occur through a channel even when aguidewire is in place in the channel.

Referring now to FIG. 16 d, yet another embodiment of flow resistor 310includes multiple slits 320 for allowing passage of a guidewire. Slits320 typically have some amount of flexibility, to allow passage of theguidewire. In some embodiments, slits 320 do not allow passage of fluid,while in other embodiments fluid may pass through slits 320. In otherembodiments, slits 320 may be combined with one or more channels toallow fluid flow. In still other embodiments, slits may be configured topermit fluid flow in one direction but not another—i.e., they mayoperate as a one-way valve.

Referring now to FIG. 17, another embodiment of a clot disruptionapparatus distal end 400 suitably includes a catheter body 302 having aninfusion lumen 404 and an aspiration lumen 410, a first expandable body314 and a flow resistor 310 with a channel 312. In this embodiment,aspiration lumen 410 includes an aspiration opening 412 and infusionlumen 404 includes a side opening 406 and a distal-end opening 408.

In an embodiment as in FIG. 17, infusion is performed via infusion lumen404 side opening 406 and distal-end opening 408 and aspiration isperformed via aspiration lumen 410 and aspiration opening 412. Guidewirepassage occurs through infusion lumen 404. Due to its positioning withininfusion lumen 404, flow resistor 310 inhibits flow only duringinfusion. In an alternative embodiment, the functionality of the lumensand openings shown in FIG. 17 may be switched, such that aspirationoccurs via infusion lumen 404 and infusion side opening 406 anddistal-end opening 408, and infusion occurs via aspiration lumen 410 andaspiration opening 412. In that embodiment, flow resistor 310 inhibitsflow during infusion and not during aspiration. Other embodiments arecontemplated, for example in which flow resistor 310 inhibits flow inmore than one lumen, in which no flow resistor is used, and the like.Generally, any suitable configuration of a clot disruption apparatusdistal end for providing preferential or predominant fluid flow from atleast one side opening relative to a distal-end opening is contemplatedwithin the scope of the invention.

Referring now to FIGS. 18 a and 18 b, another embodiment of a clotdisruption apparatus distal end 500 suitably includes a catheter body302 having an infusion/aspiration lumen 304, a flow resistor 512, and afirst expandable body 314. In this embodiment, catheter body 302 furtherincludes a flow resistor infusion lumen 510 and a flow resistor infusionopening 506 and the clot disruption apparatus includes a flow resistorinfusion port 508 at a proximal location. Infusion/aspiration lumen 304further includes a side opening 306 and a distal-end opening 308. Flowresistor 310 comprises a compliant membrane 502 and an attachmentmechanism 504.

Generally, in an embodiment as in FIGS. 18 a and 18 b, when it isdesired to inhibit flow through distal-end opening 308 using flowresistor 310, an infusate may be infused into flow resistor infusionport 508, through flow resistor infusion lumen 510 and flow resistorinfusion opening 506, to pressurize and thus move compliant membrane502. Compliant membrane 502 is typically attached to an inner surface ofinfusion/aspiration lumen 304 by any suitable attachment mechanism 504or adhesive device. When flow inhibition is no longer desired, infusatein flow resistor 512 may be discharged or otherwise released, to allowcompliant membrane to assume its original shape. In various embodimentsand configurations, compliant membrane 502 and flow resistor 512 ingeneral may be configured to allow no passage of fluid, some passage offluid, and/or passage of a guidewire.

Referring now to FIG. 19, yet another embodiment of a flow resistor 600may comprise a ball valve. Such a valve suitably includes a ball 604, achannel 602, a valve entrance 610, a valve exit 608, and a side housing606. In one embodiment, when a guidewire (not shown) is inserted throughchannel 602, the guidewire moves ball 604 to a position within sidehousing 606. When the guidewire is not within channel 602, ball 604 isfree to move anywhere within the valve. During infusion of fluid fromproximal (P) to distal (D), ball 604 will naturally be moved by thefluid to a position adjacent valve exit 608, as shown by the darkenedarrow, and will partially or wholly block fluid flow through valve exit608. During aspiration of fluid from D to P, ball 604 will naturally bemoved by the fluid to a position adjacent valve entrance 610, as shownby the hollow arrow, and will partially or wholly block fluid flowthrough valve entrance 610.

Referring now to FIGS. 20 a-g, one embodiment of a method for disruptingclot according to the present invention is shown. Many various methodsaccording to the present invention may be used for disrupting clot. Forexample, various steps may be added to or deleted from the process shownin FIGS. 20 a-g, various additional apparatus may be used, differentapparatus may be substituted, the order of steps may be changed and/orthe like, without departing from the scope of the present invention.Therefore, the exemplary methods described in FIGS. 20 a-g and FIGS. 21a-g are provided for exemplary purposes only and should not limit thescope of the invention.

That being said, with reference to FIG. 20 a, a first step in a methodfor clot disruption includes positioning a catheter body 702 within ablood vessel 706 at the site of a clot 706. Catheter body 702 includes adistal balloon 708, a proximal balloon 710, a side opening 712, and adistal-end opening 714. Typically, catheter body 702 will be positionedwithin blood vessel 704 by passing body 702 along a guidewire 716.

In a next step, as in FIG. 20 b, distal balloon 708 is inflated andguidewire 716 removed. From catheter body 702, as designated by theproximal-pointing arrow. In other embodiments, methods include leaving aguidewire in place during infusion, clot disruption, and/or aspiration.As described above, various embodiments provide minimal fluid flowthrough distal-end opening 714 with a guidewire in place, while otherembodiments provide for no flow through distal-end opening 714 with theguidewire in place.

Next, as in FIG. 20 c, proximal balloon 710 is inflated and an agent toenhance clot disruption, such as a thrombolytic agent, is infusedthrough side opening 712 and distal-end opening 714 (designated byarrows). In some embodiments, infusion may begin before inflatingproximal balloon 710. In other embodiments, infusion, clot disruptionand aspiration may all be performed without inflating proximal balloon710. Alternatively, infusion may commence concurrently with proximalballoon 710 inflation. Generally, as described in detail above, infusionis performed preferentially through side opening 712, relative todistal-end opening. This may be accomplished by providing a distal-endopening 714 with a smaller cross-sectional area than side opening 712,by providing a flow resistor within catheter body 702, or by acombination of the two.

In FIG. 20 d, with the assistance of the infused agent, clot 706 beginsto disrupt or dissolve. Additionally, because some infusion occursthrough distal-end opening 714, secondary clot 718 distal to distalballoon 708 is also disrupted/dissolved. Generally, the majority of theinfused agent, which was distributed through side opening 712, is heldwithin the blood vessel 704 in an area between proximal balloon 710 anddistal balloon 708. Containment of the infused substance largely withinthis area serves to enhance the clot disruption process and to preventside effects which may occur from systemic distribution of the agent.

Next, in FIG. 20 e, proximal balloon 710 is deflated and aspiration ofblood, disrupted clot 706, infused agent, and disrupted secondary clot718 commences. Again due to the relative cross-sectional areas of sideopening 712 and distal-end opening, due to the presence of a flowresistor, or both, aspiration occurs preferentially or predominantlythrough side opening 712. In other embodiments, aspiration may occurthrough a separate lumen with one or more separate openings. Alsoalternatively, aspiration may begin before proximal balloon 710 isdeflated or while proximal balloon 710 is deflating.

In FIG. 20 f, disrupted and dissolved clot has been aspirated from bloodvessel 704 and guidewire 716 has been repositioned in catheter body 702,through distal-end opening 714. Finally, in FIG. 20 g, catheter body 702is beginning to be removed from blood vessel 704, by passing catheterbody 702 proximally over guidewire 716 (designated by proximallydirected arrows). Guidewire 716 is then removed from blood vessel 704(not shown).

Referring now to FIGS. 21 a-g, another embodiment of a method fordisrupting clot is shown. The method first includes positioning acatheter body 802 in a blood vessel 804 at a location for disruptingclot 806 by passing catheter body 802 over a guidewire 816. The catheterbody 802 suitably includes a distal balloon 808, a side opening 812 anda distal-end opening 814 communicating with a first lumen (not visible),and second side opening 820 communicating with a second lumen (notvisible).

Next, in FIG. 20 b, distal balloon 808 is inflated when catheter body802 has been positioned in a desired location within blood vessel 804.Guidewire 816 is left in place within catheter body 802, the distal endof guidewire 816 protruding from distal-end opening 814. As in FIG. 21c, an agent is then infused preferentially from side opening 812, with asmall amount of fluid flowing or dripping from distal-end opening 814(designated by arrows). This small amount of agent/fluid may helpdissolve smaller, secondary clot 818 distal to distal balloon 808 intoharmless particles or dissolved material.

In FIG. 21 d, clot 806 and secondary clot 818 have been disrupted by theagent. In FIG. 21 e, clot 806, blood and/or agent is aspirated by secondopening 820 and second lumen. When a desired amount of disrupted clot806 is aspirated, as in FIG. 21 f, distal balloon 808 is deflated.Finally, as in FIG. 21 g, catheter body 802 is withdrawn from bloodvessel 804 over guidewire 816. Guidewire 816 may then be removed fromblood vessel 804 (not shown). As previously mentioned, FIGS. 21 a-gdescribe only one embodiment of a method of the present invention, andmany additional embodiments are contemplated. For example, aspirationand infusion may occur through the opposite lumens from those shown inFIGS. 21 a-g. Alternatively, guidewire 816 may be removed during aportion of the procedure. These and/or other changes may be made withoutdeparting from the scope of the present invention.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

1. An apparatus for disrupting a clot over a luminal length of a bloodvessel, the apparatus comprising: a catheter body comprising a proximalend and a distal portion having at least one lumen allowing passage of awire or agitator, the distal portion of the catheter body having atleast one port formed therein so as to permit fluid flow from the lumen;and an agitator that is rotatable and/or axially translatable formechanical disruption of a clot in a blood vessel, the agitatorcomprising a non-linear region disposed in the catheter body lumen suchthat the at least one port is positioned along a distal portion of thenon-linear region and the catheter body assumes the non-linear shape ofthe non-linear region of the agitator along a length of the non-linearregion.
 2. The apparatus of claim 1, wherein the non-linear regioncomprises a helical, spiral, serpentine, zig-zag, alternating, or randomgeometry.
 3. The apparatus of claim 1, wherein the non-linear regioncomprises a first helical section and a second helical section formingan alternating helical geometry.
 4. The apparatus of claim 1, the distalportion of the catheter body having a plurality of ports formed along alength of the body.
 5. The apparatus of claim 4, wherein the non-linearregion of the agitator is disposed in the catheter body lumen such thatat least some ports of the plurality are positioned along a length ofthe non-linear region.
 6. The apparatus of claim 4, wherein thenon-linear region of the agitator is disposed in the lumen such that oneor more ports of the plurality are distal to the non-linear region. 7.The apparatus of claim 4, two or more ports of the plurality havingdifferent cross-sectional areas.
 8. The apparatus of claim 4, at leastone of the ports of the plurality having a cross-sectional area that islarger compared to a proximally located port.
 9. The apparatus of claim1, further comprising one or more balloons expandable so as to reduceblood flow through a region in a blood vessel in which the catheter bodyis disposed.
 10. The apparatus of claim 9, further comprising a pair ofballoons axially spaced-apart along the catheter body.
 11. An apparatusfor disrupting a clot in a blood vessel, the apparatus comprising: acatheter body comprising a proximal end and a distal portion having atleast one lumen, the distal portion of the catheter body having at leastone port fowled therein so as to permit fluid flow from the lumen; andan agitator that is rotatable for mechanical disruption of a clot in ablood vessel, the agitator comprising a non-linear region disposed inthe catheter body lumen such that the at least one port is positionedalong a distal portion of the non-linear region; wherein the agitator isaxially translatable with respect to the catheter body so that thenon-linear region can be moved in a proximal or distal direction alongthe catheter body; and wherein the non-linear region defines anon-linear region of the catheter body.
 12. The apparatus of claim 11,wherein the non-linear region comprises a helical, spiral, serpentine,zig-zag, alternating, or random geometry.
 13. The apparatus of claim 11,wherein the non-linear region comprises a first helical section and asecond helical section forming an alternating helical geometry.
 14. Theapparatus of claim 11, the distal portion of the catheter body having aplurality of ports formed along a length of the body.
 15. The apparatusof claim 14, wherein the non-linear region of the agitator is disposedin the catheter body lumen such that at least some ports of theplurality are positioned along a length of the non-linear region. 16.The apparatus of claim 14, wherein the non-linear region of the agitatoris disposed in the lumen such that one or more ports of the pluralityare distal to the non-linear region.
 17. The apparatus of claim 14, twoor more ports of the plurality having different cross-sectional areas.18. The apparatus of claim 14, at least one of the ports of theplurality having a cross-sectional area that is larger compared to aproximally located port.
 19. The apparatus of claim 11, furthercomprising one or more balloons expandable so as to reduce blood flowthrough a region in a blood vessel in which the catheter body isdisposed.
 20. The apparatus of claim 19, further comprising a pair ofballoons axially spaced-apart along the catheter body.